There are already known numerous adhesive patches for skin test referred to as "patch tests", comprising an absorbent patch and an adhesive support, such as for example, a cloth of the "Sparadrap" type, a cloth with adhesive character. At the time of use, the operator puts on the absorbent part a test liquid, following which the patch is applied to the skin, for example, on the arm or on the back of the patient.
The presently known devices present numerous drawbacks. First of all, the test substances used, especially the allergens such as dinitrochlorobenzene present serious dangers of sensitizing for the persons frequently exposed to their contact, which is the base for the operators which must place the substance on the absorbent part, at the time of application of the patch test. These drawbacks are further increased by the necessity of preparing those solutions shortly before use, or at times, at the time of use, especially in the case of unstable and difficult to handle allergens. In second place, it is either difficult or even impossible to execute in that manner a homogeneous application of the substance to the skin. It often happens that there are obtained either local overdoses which may cause irritations, or other serious reactions in the patient, or even local insufficient doses which then result in an absence of reaction leading to an erroneous interpretation. Finally, the contours of the skin zone receiving the application of substance often present an irregular shape which may prevent the reading of a positive reaction when said reaction is weak, or which may render difficult an interpretation of the intensity of the reaction.
The classical approach to using dinitrochlorobenzene (DNCB), that is referred to hereinafter, is described by Epstein and Kligman in the "Journal Investigational Dermatology", Vol. 31, pages 103-108. That procedure, now slightly modified, is described by Lynn E. Spitler in "Manual of Clinical Immunology", Chapter 6, pages 56-57.
The disadvantages associated with the classical procedure for using DNCB include, but are not limited to, the following:
1. It is necessary, prior to use, to dissolve a specified amount of DNCB in acetone. Such a step always introduces the possibility for error in calculating the amount of DNCB to be added to a specific amount of acetone. It is well known that preparation of products by a user just prior to use is frowned upon by the Food and Drug Administration. The F.D.A. has a very strong preference for accurately controlled and prepackaged doses supplied by competent manufacturers.
2. The DNCB solution must be kept in a refrigerator and protected from light following preparation. Light is very destructive to DNCB. After two weeks, under the most favorable conditions of storage, the solution of DNCB must be discarded. Freshly prepared DNCB must be made up every two weeks. Another factor related to this particular approach is that acetone evaporates rapidly, and even under the most desirable conditions, the intensity of the dose can change over the two-week period of storage.
3. The individual who is responsible for preparing the DNCB solution can easily be sensitized by an accident in which the solution comes into contact with the skin. Those who prepare DNCB solutions are advised to wear rubber gloves. Even with the rubber gloves, accidental sensitization cannot be prevented.
4. It is not possible to apply the DNCB solution uniformly within the 2-3 cm. diameter of the metal ring. In some cases, the application will be stronger in one area than in another. Consequently, one does not gain uniform administration of DNCB to the complete area of the circle that is approximately 2-3 cm. in diameter. In addition, the DNCB application is not always contained in the area defined by the metal ring. If the DNCB seeps out around the edge of the ring, then an irregular reaction occurs. Reactions range from reasonably well defined circles to poorly defined circles. In some cases, the reaction may be quite irregular.
5. The classical method referred to previously does not provide for good dose control. In some cases, the dose may be too light, and in other cases, it may be to intense, causing burning of the skin. There is no way to insure a uniform administration of dose. Consequently, the dose will vary some from patient to patient.
6. The acetone used in the preparation of DNCB will evaporate rapidly, while the DNCB crystallizes on the skin. This creates difficulty in knowing the amount of DNCB that actually penetrates or migrates into the skin.
7. The nature of the classical method is such that it does not provide an adequate pharmaceutical form that lends itself to precise control, such as chemical analysis and animal safety testing before use. This point relates closely to Point 1.
8. The classical procedure does not allow for a standardized does. This was stated earlier, but not quite in the same terms. A standardized dose will become significant and more clearly understood when we describe in detail the instant invention.
9. The classical procedure is highly inconvenient, both to the administrator and to the patient receiving it. The administrator can and does inadvertently become sensitized by DNCB during the process of administration.
10. The solution of DNCB is highly unstable. Even during the two-week storage period, there can be a substantial variation in the concentration of the solution due to evaporation of acetone. We touched on this subject earlier, but this statement boils it down somewhat more precisely.
The device hereinafter disclosed for applying DNCB as a patch test will include the following advantages:
1. The product is prepared in its final pharmaceutical form by the manufacturer, and not by the user, making possible a very accurate procedure that provides exactly the same product from lot to lot. The manufacturer is able to conduct precise chemical measurements on the product, as well as animal tests for safety.
2. The product is stable and usable at the labeled strength for a period of time exceeding one year when stored under recommended conditions. This long-term stability of the product is an important advantage.
3. The product is packaged in such a way that the DNCB is completely and safely sealed. When carefully administered, there is virtually no chance for the user to become sensitized.
4. The product, by utilizing semi-synthetic glycerides, provides distinct advantages, such as stability in storage for a long period of time, and a uniformly administered dose of DNCB during the period of time that these glycerides slowly melt at the temperature of the skin to which they are exposed or applied. The circular mass of semi-synthetic glycerides provides a homogeneous and uniform administration of DNCB to the entire area of the circle, providing very consistent and uniformly circular reactions. This method eliminates burning of a section of the test site, and having reaction results that are too light at another portion of the site.
5. The Patch Test delivers the DNCB to the skin in a slow and uniform manner so that when the patch is removed, there is no residual crystalline DNCB. With the classical method, one finds at the sensitization site residual crystals of DNCB following the evaporation of acetone. Safely disposing of the residual crystals of DNCB may present a problem.
6. With the herein described product and the method of delivery involving semi-synthetic glycerides, the total dose used for initial sensitization is only 100 mg. With the classical procedure described earlier, the sensitizing dose utilized is 2,000 mg., or a dose twenty times greater than that used with the herein described product. The product provides superior clinical results from a greatly reduced dose, constituting an unexpected result that should create patentability. There have been previous attempts to reduce the dose through the use of vehicles such as corn oil, but these methods have failed to provide the very low, but extremely effective, dose made possible by the new product.
7. On the first visit, the patient is sensitized by the product using a 100 mg. dose. During a second visit, ten to twelve days after the sensitizing dose, the results are read. A very high percentage of patients will exhibit a spontaneous systemic primary reaction referred to as a "spontaneous flare". The product provides a greater incidence of "spontaneous flare" than the classical method or any other methods that have been employed.
8. The method for using the product provides a well defined, circular reaction, while the classical method can provide reactions ranging from well defined to substantially irregular. The reaction from the product tends to be uniform over the entire circular area, while the reaction from the classical method may vary considerably over the area on which DNCB was applied. The well defined circular reaction, with uniformity of surface area, makes the reading of results easier and more accurate.
The present invention has as its purpose to remedy those various drawbacks and to give a patch for skin tests which requires no preparation at the time of use, thus eliminating practically all dangers of contact between the substances and the operator, and further making it possible to apply to the skin a homogeneous (even) amount of substance, accurately dosed and spread over a constant area, this appreciably helping the reading and the interpretation of the reactions.
The present invention also has as its purpose to supply such patches for skin tests which may be kept for a long period of time, while keeping the qualities of the substances to be tested, especially with respect to volatile allergens or those applied in small doses.
The patches according to the present invention indeed make possible an excellent protection of the substances to be tested with respect to external phenomena such as oxidation, the effect of light, humidity, etc. It also makes possible, at least in some cases, the modification of the test application procedure, by causing with sufficient reproductibility spontaneous primary reactions which render useless a second application, as is generally done now. Finally, it also makes it possible to appreciably decrease the doses administered, and consequently the dangers of accident or of slight illness, while ensuring reactions having the desired reproductibility and safety.
The present invention has as its object an adhesive patch for skin tests comprising an adhesive layer on which there is placed, in its central part, a first layer of aluminum sheet or of a similar metal, covered with a synthetic material, with a small plate or patch made of absorbent material and which contains a dose of the test substance, said plate or patch being affixed to the center of said layer, and of a second layer of a sheet of aluminum or of a similar metal, said second layer being sealed to the first one as close as possible to the periphery of the absorbent material.
In a preferred form of execution, the second external layer is preferably provided with a simple and dependable means making its application and its removal possible. The first layer placed between the adhesive sheet and the absorbent material preferably is covered with a synthetic material such as polyethylene, a polyvinyl resin, a polyalkylvinyl resin, polyvinylidene chloride, a polyvinylic copolymer, a polyacrylic copolymer etc . . . , for example. In general it is possible to use all resins or copolymers which are suited to be applied on a sheet of aluminum or of a similar metal. The synthetic material renders possible the sealing of the second external layer on the first one, and it also makes it possible to fix the absorbent material.
By the expression "similar metal" it must be understood according to present invention all metals which are able to be laminated in thin and flexible sheets. Among those metals capable of being use, it is possible to mention in addition to aluminum, tin and lead. The thickness of the metal sheets and more particularly of aluminum sheets is generally of about at least 25 microns.
The absorbent material preferably presents itself in the form of the small plate or round piece of filter paper or of blotting paper, the area of which ranges between 2 and 7 cm.sup.2.
The tight (leakproof) sealing between the two layers must be done as close as possible to the periphery, and preferably at the periphery itself of the round piece or plate of absorbent material, so as to avoid all danger of contamination of a part of the first layer by the substance to be tested.
Indeed, if the tight sealing were not executed as close as possible to the periphery of the small disc or plate of absorbent material, it could happen that, through an evaporation or sublimation process, partial condensation of the substance to be tested would take place on the first layer, a situation which would render reading of the reaction difficult because of its non-regular area.
In an especially favored form of execution, the test substance, especially in the case of a substance such as dinitrochlorobenzene, dinitrofluorobenzene or other allergens such a oxazolone, beryllium fluoride or paraphenylenediamine, is mixed with a suitable quantity of an excipient which is more or less solid at room temperature, but capable of softening or of melting when in contact with the skin, without being volatile under heat.
Among those materials capable of being used as excipients, it is possible to mention the glycerides of fatty acids in C.sub.12 -C.sub.18 and especially the palmitostearic glycerides, the polyoxyethylenated glycerides of fatty acids, the alkyl esters of fatty acids such as the isopropyl myristate or palmitate, the fatty acids, the fatty alcohols in C.sub.12 -C.sub.18 as well as ethers of said fatty alcohols and the esters of glycols.
There are preferably used, according to the invention, semi-synthetic glycerides, the melting point of which ranges between 33.degree. and 45.degree. C., and especially those sold by the Gattefose Co. under the commercial name of "SUPPOCIRE".
Hydrosoluble excipients may also be used, either alone or mixed with the preceding ones, such as propyleneglycol, glycerin, polyoxyethylenated glycols and alcohols.
Surprisingly, it has been observed that, for example, in the case of a much used allergen such as dinitrochlorobenzene presented in a suitable excipient of that type, it was possible both appreciably to decrease the dose of allergen and systematically to cause a primary spontaneous reaction, making it possible to perform the test in a single application.
Such results are not explained only by the fact that in the patch according to the invention the allergen substance is stabilized before the use of the patch and also while said patch is applied to the skin, but also by an action which facilitates and regularizes the penetration of the skin by the allergen substance.
Thus, in the case of an adhesive dinitrochlorobenzene patch according to the invention, the quantity of allergen substance needed to sensitize the subject preferably ranges between 60 and 150 gammas (1 gamma=1 microgram), the concentration being less than 50 gammas per square centimeter of area of the absorbent material. It is, however, possible, of course, to use more important quantities, but experience proves that it is useless, while in the usual tests doses of at least 300 gammas/cm.sup.2 normally are necessary. The most classical technique consists in a total application of 1,000 or even of 2,000 gammas. In the same manner, reaction revealing patches may contain smaller doses, of 1 to 10 gammas, for example, while usually doses of 20 to 50 gammas, and even 100 gammas are necessary.
The invention also has as its object a process for the fabrication, in continuous process, of the adhesive patch, characterized by the fact that there is made to pass by a strip of aluminum or of a similar metal, covered with a synthetic material and meant to constitute the first layer located under the absorbent material; that there are affixed, at regular intervals plates or small round discs of absorbent material to said strip; that there is spread over each small round disc a given quantity of the substance and possibly of its excipient in a solution, that the solvent is evaporated, for example, by causing the strip to run through an air current; that there is brought, on said strip, a second strip which constitutes the second layer; that the two layers are sealed together as close as possible to the periphery of said small round discs, after which there are carried out the various operations of cutting and of connection with a strip of adhesive support, at regular intervals, said strip of adhesive support being then preferably covered with a corrugated strip which protects the adhesive (material) before the individual patches are finally cut out.
According to the present invention, the second layer may be identical with or different from the first one. The leakproof seal between the two layers preferably is done by heat, the temperature being a function of the nature of the synthetic material used.
In a preferred mode of execution of the invention, in which there are manufactured patches for dinitrochlorobenzene skin tests or of tests with other closely related substances, it is advantageously possible to dissolve the substance and its excipient in a common solvent, for example, in trifluorotrichloroethane or in a mixture of acetone and chloroform.
Other advantages and characteristics of the invention will appear upon reading of the following description, given as an example which is not limitative, and which refers to the attached drawings in which: